Design, synthesis and investigation of acetylcholinesterase-butyrylcholinesterase inhibitory activities of secnidazole derivatives

Aim: The objective is to design, synthesize, and investigate the inhibitory effects of certain seknidazole derivatives (1a-h) on the enzymatic activities of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Material and Method: The inhibitory effects of the synthesized compounds on AChE and BChE enzymes were investigated using the Ellman method. Donepezil and Ellman's reagents were used as standard substances. Results: Our results indicate that all compounds exhibit significant inhibitory effects against both AChE and BChE compared to the reference compound donepezil. In particular, compound 1h demonstrated more effective inhibition for both enzymes. It exhibited the highest potency with Ki values of 0.024±0.009 nM for Electrophorus electricus AChE (EeAChE) and 0.087±0.017 nM for equine serum BChE (eqBChE). Additionally, molecular docking studies provided valuable insights into the interaction mechanisms of these compounds within the active sites of the AChE and BChE crystal structures (PDB IDs: 4EY7 and 4BDS, respectively). Conclusion: Seknidazole derivatives have been shown to be promising functional agents for the treatment of Alzheimer's disease (AD). The dual inhibition of these enzymes is considered a promising strategy, particularly for the treatment of neurological disorders such as AD.